Lena Böhn

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Lena Böhn

Department of Internal Medicine and Clinical Nutrition

Institute of Medicine

Sahlgrenska Academy at University of Gothenburg

Gothenburg 2015

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Food-related gastrointestinal symptoms, nutrient intake and dietary interventions in patients with irritable bowel syndrome

ISBN 978-91-628-9245-6 (Printed edition) ISBN 978-91-628-9248-7 (Electronic edition) http://hdl.handle.net/2077/37527

Printed in Gothenburg, Sweden 2015 Ineko AB, Gothenburg

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To Amanda, Jesper and Anders

“Life begins at the end of your comfort zone”

N. D. Walsch

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Department of Internal Medicine and Clinical Nutrition, Institute of Medicine Sahlgrenska Academy at University of Gothenburg

Gothenburg, Sweden

Food is a recurrent problem in irritable bowel syndrome (IBS) and it is common to exclude foods, which could lead to a reduced nutrient intake. Perceived food intolerance is very common in IBS, but if specific or more generalized food intolerance is the problem is unknown. Incompletely absorbed carbohydrates (fermentable oligo-, di-, mono-saccharides and polyols, FODMAPs) can trigger gastrointestinal (GI) symptoms, but if an enzyme (Į-galactosidase), capable of digesting oligosaccharides, is able to relieve meal-related symptoms, or if a diet low in FODMAPs is more efficient in reducing symptoms than traditional dietary advice is not known.

Methods: Paper 1: The nutrient intake (from food diaries) in IBS patients was compared with a sex-and-age matched population from a Swedish national dietary survey. Paper 2: IBS patients completed questionnaires to assess self-reported food intolerance and the association with other clinical and demographic variables. Paper 3: In a randomized, double-blind, placebo-controlled, crossover trial; the effect of Į- galactosidase on GI symptoms in IBS patients after carbohydrate-rich meals was investigated. Paper 4: In a randomized, single-blind, parallel group, four-week trial;

the effect on IBS symptoms of a low FODMAPs diet was compared with traditional dietary advice in IBS.

Main results: The nutrient intake in IBS patients was similar to the Swedish general population. Eighty-four percent of IBS patients reported food-related GI symptoms, especially after intake of foods rich in incompletely absorbed carbohydrates and fat.

Self-reported food intolerance was associated with more severe IBS symptoms and reduced quality of life. Į-galactosidase was not superior to placebo in reducing GI symptoms after carbohydrate-rich meals in IBS patients. Fifty percent in the low FODMAPs group responded favorably to the dietary intervention (reduced GI symptoms), and 46 % were responders in the group who received traditional dietary advice.

Conclusions: Despite a high degree of self-reported food intolerance in IBS, the majority of these patients seem to have adequate nutrient intake. A low FODMAPs diet and traditional IBS dietary advice, but not Į-galactosidase capsules, reduce symptom burden in patients with IBS.

Keywords: irritable bowel syndrome, gastrointestinal symptoms, diet ISBN: 978-91-628-9245-6

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tarmsjukdom som kännetecknas av smärta och/eller obehag i magen i kombination med avföringsrubbning. Mat är ett återkommande och centralt problem för många patienter med IBS, som ofta uppger att de undviker ett eller flera livsmedel, vilket kan leda till minskat näringsintag. Upplevd födoämnesintolerans är mycket vanlig i patientgruppen men man vet inte om överkänslighet för något enskilt födoämne kan påvisas. Man har sett att inkomplett absorberbara kolhydrater, s.k. FODMAPs, kan orsaka IBS-symtom, men om ett enzym som kan underlätta upptaget av kolhydrater i tunntarmen kan lindra måltidsrelaterade symtom eller om en kost med lågt FODMAPs-innehåll medför färre symtom än traditionella kostråd är okänt.

Metod: För att bedöma hur IBS-patienter äter jämförde vi näringsintaget (kostdagböcker) från 187 IBS-patienter med en ålders- och könsmatchad kontrollgrupp (384 personer) från en nationell kostundersökning. För att sedan undersöka vilka livsmedel som IBS-patienter anser ge mag-tarmsymtom, fyllde 197 IBS-patienter i frågeformulär, där de specificerade mag-tarmsymtom efter intag av 56 olika livsmedel. Vi genomförde sedan två behandlingsstudier: Först undersökte vi om ett enzym (Į-galaktosidas) kunde avhjälpa symtom som uppkom i samband med kolhydratrik mat hos 20 IBS-patienter. Efter det undersökte vi hos 75 IBS-patienter om en kost med lågt FODMAPs-innehåll är mer effektiv än traditionella kostråd vid IBS för att lindra mag-tarmsymtom.

Resultat: IBS-patienternas näringsintag skiljde sig inte nämnvärt från normalbefolkningen, trots att 84 procent av patienterna rapporterade mag- tarmsymtom efter intag av olika livsmedel och då framför allt efter livsmedel som innehåller fett och inkomplett absorberade kolhydrater. Mag-tarmsymtom efter intag av kolhydratrika måltider lindrades inte mer av Į-galaktosidas jämfört med placebo.

Femtio procent av testgruppen svarade positivt (minskade symtom) på låg- FODMAPs-kosten och 46 % svarade positivt i gruppen som fått traditionella kostråd.

Slutsatser: Patienter som har IBS äter ungefär som normalbefolkningen i Sverige och har som grupp ett adekvat näringsintag. De flesta IBS-patienter upplever att kost som innehåller mycket fett och inkomplett absorberbara kolhydrater orsakar symtom.

Det verkar inte hjälpa IBS patienter att ta Į-galaktosidas i samband med kolhydratrik måltid för att lindra mag-tarm-symtom. Emellertid verkar kostråd vara effektivt för att minska mag-tarmsymtom vid IBS och de kostråd vi testade bör i framtiden sannolikt kombineras i ytterligare studier av deras symtomlindrande egenskaper.

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Roman numerals.

I. Böhn L, Störsrud S, Simrén M.

Nutrient intake in patients with irritable bowel syndrome compared with the general population.

Neurogastroenterol Motil. 2013;25:23±e1.

II. Böhn L, Störsrud S, Törnblom H, Bengtsson U, Simrén M.

Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life.

Am J Gastroenterol. 2013;108(5): 634-641.

III. Böhn L, Störsrud S, Törnblom H, Van Oudenhove L, Simrén M.

A randomized double-blind placebo-controlled study:

Effects of the enzyme alpha-Galactosidase on gastrointestinal symptoms in IBS patients.

Submitted for publication.

IV. Böhn L, Störsrud S, Liljebo T, Collin L, Lindfors P, Törnblom H, Simrén M.

A randomized, controlled trial comparing a diet low in FODMAPs with traditional dietary advice in patients with IBS.

Submitted for publication.

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ABBREVIATIONS ... IV

1 BACKGROUND ... 1

1.1 Irritable bowel syndrome ... 1

1.2 Food and GI physiology ... 3

1.3 Assessment of nutrient intake ... 5

1.4 Food and IBS ... 7

1.5 Effects of food on GI function in IBS ... 9

1.5.1 Fat ... 9

1.5.2 Carbohydrates... 10

1.5.3 Other factors ... 12

1.6 IBS and dietary advice ... 13

1.6.1 Carbohydrates... 13

1.6.2 Probiotics ... 15

1.6.3 Food elimination diets ... 16

1.6.4 Other common dietary approaches ... 16

2 AIMS ... 17

Paper I ... 17

Paper II ... 17

Paper III ... 17

Paper IV ... 17

3 PATIENTS AND METHODS ... 18

3.1 Patients ... 18

3.2 Questionnaires ... 18

3.3 Dietary intake ... 21

3.4 Breath test ... 22

3.5 Dietary interventions & assessment of treatment effect... 23

3.6 Research design... 26

3.7 Statistics ... 28

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4.1 Patients ... 30

4.2 Paper I. Nutrient intake in IBS ... 31

4.3 Paper II. Food-related GI symptoms in IBS ... 33

4.4 Paper III. Symptoms after carbohydrate-rich meals in IBS: The effect of enzyme supplementation ... 34

4.5 Paper IV. Low FODMAPs diet vs. traditional dietary advice in IBS . 37 5 DISCUSSION ... 41

5.1 Subjects ... 41

5.2 Dietary assessment ... 43

5.3 Dietary intake ... 43

5.4 Self-reported food-related GI symptoms ... 44

5.5 Effect of α-galactosidase on GI symptoms ... 45

5.6 Dietary advice in IBS ... 46

6 CONCLUSION ... 48

7 FUTURE PERSPECTIVES ... 49

ACKNOWLEDGEMENT ... 50

REFERENCES ... 51

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BMI Body Mass Index BSF Bristol Stool Form

FFQ Food Frequency Questionnaire

FODMAPs Fermentable Oligo-, Di-, Monosaccharides And Polyols GI Gastrointestinal

GOS Galacto-oligosaccharides

HAD Hospital Anxiety and Depression scale IBS Irritable Bowel Syndrome

IBS-C IBS with constipation IBS-D IBS with diarrhea IBSQOL IBS Quality of Life

IBS-SSS IBS-Severity Scoring System

MFI-20 Multidimensional Fatigue Inventory-20 PHQ-15 Patient Health Questionnaire-15 VSI Visceral Sensitivity Index

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Irritable bowel syndrome (IBS) is a common functional gastrointestinal (GI) disorder that affects persons world-wide, and a recent systematic review of eighty cross-sectional surveys found a global prevalence of 11.2 % in the adult population (with significant geographical differences ranging from 1.1

% to 45 %) (1). This makes IBS one of the most common GI disorders, and it is one of the leading causes for consultations in gastroenterology outpatient clinics, as well as in primary care (2). However, a large proportion of subjects with the disorder do not seek medical advice (2). IBS is more common in women than in men, with a female/male ratio of approximately 2 to 1 (3), and the peak prevalence is between the ages of 20 and 30 years (4).

IBS, which is the most common functional bowel disorder, is characterized by abdominal pain and/or discomfort related to abnormal bowel habit (diarrhea, constipation or mixed diarrhea and constipation), but with normal clinical routine investigations and tests (5). The etiology and pathophysiology are only partly understood (6) and available treatment options are limited (7).

IBS has profound effects on quality of life (8) and is associated with substantial costs for the society (9). Unfortunately, there are no available objective biomarkers and the diagnostic criteria have changed somewhat over the years, which make prevalence figures from different time periods difficult to compare. The first diagnostic criteria developed for IBS was the Manning criteria from 1978, which included abdominal pain relieved by defecation, more frequent stools and/or looser stools with onset of pain, passage of mucus per rectum, feeling of incomplete emptying, and abdominal distension (10). Later, groups of multinational experts have refined the diagnostic criteria for IBS and other functional bowel disorders in the Rome I (11), II (12) and III (5) criteria, respectively. In Table 1 the most recent diagnostic criteria for IBS, the Rome III criteria, is shown. In order to make a confident diagnosis, a limited number of routine investigations are recommended, and normal results are expected. Moreover, in order to rule out more severe GI diagnoses as an explanation for the symptoms, it is considered essential to UXOHRXW³UHGIODJV´RUDODUPV\PSWoms, such as symptom onset after 50 years of age, rectal bleeding, recurrent vomiting, fever, and family history of colon cancer. The presence of any of these necessitates a more thorough clinical

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investigation before an IBS diagnosis can be made (2, 13). Based on the dominant stool form or consistency, IBS is also subtyped into IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), mixed IBS (IBS-M), and unsubtyped IBS (IBS-U) (5).

Table 1. The Rome III Diagnostic Criteria*

Recurrent abdominal pain or discomfort** at least 3 days per month in the last 3 months associated with 2 or more of the following:

1. Improvement with defecation

2. Onset associated with a change in frequency of stool 3. Onset associated with a change in form (appearance) of stool

* Criterion fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis.

** "Discomfort" means an uncomfortable sensation not described as pain.

As stated above, the key symptoms in IBS are abdominal pain and abnormal bowel habit, but also other symptoms such as bloating, abdominal distension, flatulence, urgency, defecation straining, and feeling of incomplete bowel emptying are common (5, 14). The frequency and the intensity of GI symptoms vary substantially in IBS patients, and not everybody with symptoms seeks medical care for their symptoms. This may have different explanations, e.g. frequency or intensity of symptoms, coping abilities, cultural differences, and psychosocial factors (15). Besides, as the disorder is associated with symptoms such as flatulence, abdominal distension, diarrhea, constipation, and urgency to defecate, it is also associated with several taboos and embarrassing situations (16). Moreover, patients with IBS also often report symptoms related to other parts of the GI tract than the bowel (17), as well as multiple extraintestinal symptoms (18, 19). Backache, headache, lethargy, urinary symptoms, fibromyalgia, chronic fatigue syndrome, sleeping problems, and nausea are examples of comorbid symptoms/conditions that may co-exist with IBS (20, 21), and psychological co-morbidity is also commonly seen in IBS patients, especially in those who seek health care frequently (20, 22). The presence of multiple GI and extraintestinal symptoms in combination with typical IBS symptoms actually support a diagnosis of IBS (23).

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The pathophysiology of IBS is incompletely understood, and there seem to be several important factors in IBS which could explain the origin and causes of symptoms, such as dysregulation of the brain-gut axis, genetic factors, psychosocial factors, early family environment, abnormal gut motility and sensitivity, impaired gut barrier function, low-grade inflammation and altered gut microbiota (24-28). Genetic factors may predispose to the development of IBS, but the exact role of genetic factors in IBS is so far not well known (29).

One of the most widely studied pathophysiologic factors in IBS is visceral hypersensitivity, which is found in a substantial proportion of IBS patients, (30, 31) but whether this is due to abnormalities in the gut or in the brain, or at different sites in different individuals, is not known. The brain-gut axis is the constant communication between the central nervous system (CNS) and the enteric nervous system (ENS) of the gut. The brain influences the functions of the ENS and the gut affects the brain. The symptoms in IBS is currently believed to be caused by dysfunction in this communication (28, 32). Psychological co-morbidity and other psychosocial factors, coping abilities, daily hassles, and major life events can precede the onset of IBS and influence symptom exacerbation of IBS in susceptible persons (33). Early life trauma and abuse increase the risk of developing IBS, and socioeconomic status and social learning can influence the development and manifestation of illness behavior and symptoms in adults (34, 35). Moreover, IBS has traditionally been associated with altered GI motility, and in some patients increased frequency and irregular bowel contractions have been seen together with affected transit time through the GI tract, and in other patients an exaggerated motor response to meal ingestion has been reported (31, 36-38).

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as low-grade inflammation in the GI tract and immune activation, impaired epithelial barrier function, and altered microbiota composition and function in the colon, as well as in other parts of the GI tract (25). Taken together, the pathophysiology of IBS is complex and poorly understood and future studies need to determine the relative importance of the above mentioned factors, as well as how they interact and cause symptoms in patients with IBS.

The main function of the GI tract is to digest the food we eat in order to facilitate absorption of nutrients that can be used in various processes in our body. The digestive process includes mechanical and chemical breakdown,

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and absorption. This process starts before eating; just thinking of, tasting, smelling, chewing and swallowing food, stimulate production of gastric acid in the stomach. Then the food is chewed into smaller pieces in the mouth and is mixed with enzymes. The process continues in the stomach where the food is mixed with gastric acid and even more enzymes. Some digestion of carbohydrates and proteins takes place in the stomach; however, the final breakdown occurs in the small intestine.

When gastric acid enters the first part of the small intestine, i.e. the duodenum, the endocrine cells are triggered to neutralize the acidic intestinal content (chyme) in order to optimize the chemical effect from pancreatic digestive enzymes and bile, and also to protect the small intestine from the gastric acid. At the same time as the chyme is digested, it is transported through the GI tract in a suitable pace to make the nutrient absorption as effective as possible. The motility of the small intestine mixes and moves the content slowly forward towards the colon, until the majority of nutrients are absorbed. The intensity of the contractions is dependent on the parasympathetic and the sympathetic nervous system, the enteric nervous system and hormones. Under normal conditions, few unabsorbed nutrients are left when the chyme enters the colon. There are however a huge quantity of bacteria in the colon that can synthesize vitamin K, and break down cellulose and unabsorbed carbohydrates through fermentation. The amount of bacteria varies and for example increases when the consumption of dietary fibers is large, and treatment with antibiotics decreases the bacterial number.

Bacterial metabolism produces gases such as carbon dioxide, methane and hydrogen (39).

Carbohydrates consist of starch, glycogen, cellulose, and different saccharides. Carbohydrates must be digested into monosaccharides in order to be absorbed and this is done by different enzymes secreted from the salivary glands, stomach, pancreas, and from epithelial cells in the small intestinal brush border. The monosaccharides glucose and galactose are effectively absorbed in the small intestine into the portal vein, but the capacity to absorb fructose, another monosaccharide, is limited and dependent on the concurrent absorption of glucose. Excess fructose and other non-digested carbohydrates are transported to the colon, where they are fermented into short chain fatty acids that generally are considered to be beneficial to health (40). Fructose and also sorbitol are incompletely absorbed in the normal small intestine, and simultaneous ingestion of glucose enhances fructose absorption and malabsorption occurs only when fructose is present in excess of glucose (41).

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Proteins are digested by the enzyme pepsin to peptides in the stomach, and the major breakdown takes place in the small intestine by different proteases in the pancreatic juice. The end products are short-chain peptides and amino acids, and the epithelial cells absorb both smaller peptides and amino acids to the portal vein.

Lipids (fats) consist mainly of triglycerides. The digestion of lipids occurs exclusively in the small intestine due to the necessary addition of pancreatic lipase and bile. The end products after fat digestion are free fatty acids and mono-glycerides.

Absorption of water is very efficient in the intestine. When different substances are absorbed, water follows, through osmosis. The small intestine and the colon absorb approximately 99 % of the water.

Only a small part of the feces, from a normal diet, are undigested food, and feces consist mainly of waste products, rejected epithelial cells and colon bacteria.

Accurately measuring diet in free-living human subjects is difficult to accomplish with precision. The appropriate tool for dietary assessment will depend on the purpose for which it is needed. Different methods have been developed for the purpose of assessing dietary intake. These range from simple food lists, household survey methods, food frequency questionnaires to detailed individual weighed records collected over a period of several days. Each method has its merits, practical difficulties and associated errors that needs to be considered (42). The purpose for which the dietary assessment is needed will decide the appropriate method. The purpose may be to measure nutrients, foods or eating habits on individual levels or in a larger group of subjects. In Table 2 an overview of the most common self- report dietary assessment methods are presented. When validating dietary assessment methods, i.e. biomarker-based validation, underreporting is most often observed. Recall methods are limited by memory. Record methods are biased by the fact that the subjects are likely to change their intake and both methods are potentially affected by over-reporting of healthy foods or what the subject LV³H[SHFWHGWRHDW´

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Table 2. Overview of common self-report dietary assessment methods.

Method Description Strengths Weakness

Weighed food record (commonly 3-7 days; 7 days is

“gold standard”)

The subject weighing every item of food and drink prior to consumption in a specially designed booklet.

Widely used methods Precision of portion sizes

High respondent burden Misreporting Changing intake behavior Day-to-day variations Coding requires expertise

Estimated food record

The subjects register every item of food and drink prior to consumption in a specially designed booklet.

The portion size is estimated or household measures are used.

Widely used method

Lower respondent burden than weighed food diaries

Relatively high respondent burden

Estimation of portion size Misreporting Day-to-day variations Coding requires expertise

24-h recall

A trained interviewer asks the respondent to remember in detail all the food and drink they consumed during the previous 24 hours.

Low respondent burden

Can be administered by telephone

Requires a trained interviewer Relies on memory Estimation of portion size Single day vs day-to-day variation Coding requires expertise

Diet history

A trained interviewer asks the respondent to describe customary food and/or nutrient intakes over a relatively long period e.g.

6 months or longer.

Can be administered by telephone

Cannot be self-completed Relies on memory Estimation of portion size Coding requires expertise

Food Frequency Questionnaire

Consists of a list of foods and a selection of options relating to the frequency of consumption (i.e. times a day/daily/weekly/monthly)

Can be self-completed

Can be optically scanned

Estimation of portion size Possible over-reporting of

“healthy” foods

Traditionally, the diet-record method has been considered to be the most accurate method to assess food intake. However, the validity depends on the subjects’ willingness to cooperate. The number of consecutive days of recording often influences the compliance, the recording can interfere with normal eating behavior, and the subjects may alter their intake due to self- consciousness, being ashamed or convenience (43). The estimated method to

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assess nutrient intake is widely used, with a lower burden on respondents than the weighed food diaries. The weakness of this method is however difficulties when the investigator converts these estimates into weights that can then be used to calculate food and nutrient intake, and it is of course more time consuming for the investigator.

Alternative methods have other limitations, for instance underreporting due to limits of memory (diet history, 24-h recall method). Food-frequency questionnaires (FFQs) are designed to collect dietary information from large numbers of individuals. Depending on the length of the food list, and if portion size is not included in the questionnaire, it is not possible to measure the complete nutrient intake from these questionnaires. Validation of these self-reported dietary intake approaches, through methods with biomarkers, has unfortunately shown underreporting and systematic and random errors (44). However, only a few biomarkers (e.g. energy and protein) qualify as valid reference instruments to reflect dietary components (44). When performing studies to assess nutrient intake in a population, one has to take above-mentioned limitations into account and weigh these against the purpose of the investigation.

Food and diet concerns patients with IBS (45), and they frequently report association between food ingestion and onset or worsening of GI symptoms (46, 47). The majority of IBS patients report adverse reactions to one or more foods and consider that their symptoms are aggravated by food intake.

Several studies have investigated this and have come up with more or less the same findings, i.e. approximately two thirds of IBS patients report an association between food intake and worsening of their symptoms (46-49). In one study, female sex and anxiety seemed to predict a higher degree of food- related symptoms in IBS patients (46), which is in line with the finding that female IBS patients report more changes in their dietary habits because of GI problems than men with IBS (47).

Many IBS patients believe that food allergy or specific food intolerances can explain their symptoms (47). Food allergy is an immune response that occurs reproducibly on exposure to a specific food and can result in different symptom manifestations, including anaphylactic shock, which is a very severe condition. Food allergy is found in about 2-10 % of the general population (50), but there is no evidence to date that has suggested an increased frequency of food allergy in IBS compared to the general

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population (51-53), even though there may be a subgroup within the IBS population where a link to genuine allergy mechanisms may be involved in symptom generation (54). However, perceived food intolerance, on the other hand, which is very common in the general population (55), is even more common in IBS, as 20-65 % of IBS patients attribute their symptoms to these non-toxic and non-immune-mediated adverse reactions to food (46, 47, 56, 57), but the underlying mechanisms are not well understood. Psychological factors are common in patients with symptoms compatible with IBS who attribute their symptoms to food intolerance (46, 58), but still only explains a small proportion of the variance in symptom severity in patients with self- reported food intolerance (59), so this does not seem be the major explanatory factor for food intolerance in IBS.

Typical symptom generating foods in patients with IBS are foods rich in fat (60) and carbohydrates (61-64), as well as cabbage, onion, beans, milk, wheat, coffee, peas/beans, hot spices, deep-fried food, pizza and cream (46, 47, 65). The current opinion is that a more general food sensitivity is a plausible explanation to some of these reactions, and the potential underlying mechanisms are discussed below. The perceived food intolerance may lead to avoidance of different foods in IBS, and sometimes patients risk nutrient deficiency. Several studies report that people with IBS often avoid different food items as a way of coping with the disease, which possibly could lead to a lower intake of essential nutrients (2, 46, 47, 66, 67). However, patients with IBS seem to have a body mass index (BMI) comparable to the general population (46), and few studies have addressed nutrient intake in IBS and assessed the nutritional adequacy of their diet (68). Moreover, differences in the presence and severity of subjective food intolerance between subgroups of IBS patients are not well covered in the literature.

When comparing individuals with IBS with subjects without IBS, there is weak evidence suggesting increased incidence of lactose malabsorption in IBS patients, when using a hydrogen breath test (69-72). The importance of lactose intolerance in IBS is therefore questionable, but in some studies lactose intolerance has been reported to be of relevance for patients with IBS, and a positive effect on symptoms after lactose restriction has been demonstrated (69, 71, 73). However, there are also other studies with limited or no effect of lactose restriction in IBS patients (70), so the clinical relevance of lactose intolerance is still controversial.

Failure to completely absorb fructose in the small intestine, i.e. fructose malabsorption, is common in the general population, and is usually not linked to symptoms (74). However, in IBS patients it has been proposed that the

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presence of fructose malabsorption may be of relevance for symptom generation, even though it is probably not more common with fructose malabsorption in IBS patients than in the general population (62, 75), but also this is controversial, as opposing studies exist (76).

Fat is an important mediator of postprandial GI motor and sensory effects (77) and a potent stimulating factor of the colonic response to a meal (78). It is well known that especially large meals and meals with a high fat content are potent stimulators of the gastrocolonic response in general (79, 80), and in IBS patients in particular (81). Moreover, also in the upper part of GI tract, fat has profound effects on GI physiology, including effects on various GI peptides, with both GI and non-GI effects (82), which may also be involved in symptom generation after intake of fatty foods in IBS patients.

Abdominal pain after a meal is a common feature in IBS patients. One potential explanation behind this is the fact that the colonic hypersensitivity, seen in many IBS patients, is exaggerated after delivery of fat into the proximal small intestine. This has been studied by measuring the sensitivity to balloon distensions in the sigmoid colon before and after administration of lipids into the duodenum. A larger proportion of patients reported pain at the different pressure steps during the balloon distension after versus before duodenal lipids, and this was different from the findings in healthy controls, supporting an exaggerated sensory component of the gastrocolonic response in IBS patients (60, 83). It is tempting to speculate that this mechanism is involved in postprandial symptoms in IBS.

Another potential mechanism behind worsening of symptoms in IBS patients after meal intake is the effect of nutrients on gas transit and tolerance.

Bloating and abdominal distension are prominent symptoms in patients with IBS and other functional GI symptoms, and it has been demonstrated that IBS patients with abdominal bloating have disturbed gas transit in the GI tract and tend to accumulate gas in the GI tract and also have a reduced tolerance to gas in the GI tract (84). This is modulated by nutrients, and especially the effect from lipids on gas transit and tolerance is enhanced in patients with IBS (85).

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Taken together, lipids may worsen symptoms in IBS through different mechanisms, and probably the relative importance of these may differ between individuals.

As stated above, many patients with IBS report symptoms after intake of food items rich in different carbohydrates, and this may be related to incomplete absorption of different carbohydrates in the small intestine leading to negative effects in the colon in sensitive individuals. Traditionally, IBS patients have been encouraged to increase intake of dietary fibers (86), but many IBS patients state that their symptoms are worsened by increased fiber intake (87). Dietary fibers are non-starch polysaccharides that are mainly found in plant cell walls, and includes insoluble fibers (e.g. lignin, celluloses, and some hemicelluloses), and soluble fibers (e.g. ȕ-glucan from oats and barley, pectin and gums in psyllium) and these have well established positive effects on health in general (88). In functional GI disorders, the positive effect of dietary fibers on stool form/consistency has been used therapeutically (89) but there is still conflicting data whether increasing or decreasing intake of dietary fibers is beneficial in subjects with IBS (87, 90, 91).

Many of the food items that are rich in dietary fibers, such as cereals, wholemeal bread, vegetables and fruits, also contain large amounts of incompletely absorbed short-chain carbohydrates which may cause GI symptoms in individuals with IBS through fermentation and osmotic effects in the colon when ingested (61). In fact, in the last years several lines of evidence have emerged showing that intake of food rich in these incompletely absorbed short-chain carbohydrates, collectively called FODMAPs - Fermentable Oligosaccharides, Disaccharides, Monosaccharides And Polyols - can be responsible for symptoms in large groups of patients with IBS (92). In line with this, recent evidence has suggested that reducing the FODMAPs content is efficient in reducing symptoms in IBS and other GI conditions (64, 93-97). In the FODMAPs concept the following groups of carbohydrates are included:

x Oligosaccharides: The human GI tract lack enzymes that are able to hydrolyze certain oligosaccharides, such fructans and galacto-oligosaccharides (GOS), thus absorption of these are not possible (98). Foods that contain large amounts of

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oligosaccharides are peach, artichoke, wheat, rye, onion, legumes, chickpeas, lentils.

 Disaccharides: The dietary disaccharides, sucrose, lactose, maltose, isomaltose and trehalose are hydrolyzed by enzymes (disaccharidases) expressed by small intestinal epithelial cells. The absorption of lactose relies on the activity of the enzyme lactase in the epithelial brush border.

Of the disaccharides this is the only enzyme that is commonly deficient, as lactase deficiency is the common state in the main part of the world, leading to unabsorbed lactose passing into the colon. However it varies greatly in different ethnic groups, with the frequency of maintained lactase production being larger in northern Europeans than in Asian and African ethnic groups (99, 100). Typical foods containing lactose are milk, yoghurt, and ice-cream.

 Monosaccharides: The absorption of dietary mono- saccharides varies. Glucose and galactose are effectively absorbed in the small intestine. However, the absorption of fructose is more variable, and is dependent on the concurrent presence of glucose (101). When fructose is present in excess of glucose, malabsorption occurs, as co-ingestion of glucose enhances fructose absorption (41). Some fruits and vegetables contain large amounts of “free” fructose, for example apple, cherries, watermelon, asparagus, artichokes, and honey, and ingestion of large amounts of such food items may therefore lead to substantial amounts of fructose passing unabsorbed to the colon.

 Polyols: The ability to absorb polyols (sorbitol, mannitol, maltitol and xylitol) varies between individuals and across different polyols, and the absorption is generally slow and passive. Polyols are present in foods such as apple, apricot, cauliflower, and in all sugar substitutes that end with –ol (e.g. sorbitol, maltitol, xylitol).

The mechanisms through which FODMAPs may cause symptoms in susceptible individuals are through osmosis and fermentation. Short-chain carbohydrates are osmotically active and if they are incompletely digested or absorbed, or if the absorption process is slow, this will increase the water volume in the small intestine. They can also be fermented in the colon, leading to production of different gases. These two actions will lead to luminal distension that may aggravate symptoms in subjects with IBS (92, 102, 103). The increased luminal water may in addition to distension also

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lead to looser stools. Moreover, besides gases, the colon bacteria also produce osmotically active short-chain fatty acids with effects on sodium and water absorption, as well as on motility. However, not all subjects that ingest large amounts of FODMAPs report symptoms (76) and the presence of visceral hypersensitivity or other factors may be an additional prerequisite to have symptoms after FODMAPs ingestion (92, 93).

Based on these findings, a diet with low FODMAPs content has been tested in IBS with promising results, i.e. marked improvement of GI symptoms results in the majority of patients (94-96). The low FODMAPs diet implies a carbohydrate restricted diet, and the potential problem is that it is quite intrusive and difficult to follow, and the long-term effects are still not known, with potential negative effects on gut microbiota composition (97, 104).

Gluten has recently been put forward as an important dietary factor to consider in patients with IBS, even in the absence of celiac disease (105). The mechanism behind the potential negative effects of gluten in IBS is still debated, but effects on intestinal permeability (106), a FODMAPs effect (107) or immune mechanisms (108) are plausible. Other dietary factors that may affect GI function negatively in IBS patients include alcohol and caffeine (46, 47).

Recently, alterations in gut microbiota composition and function have been put forward as an important factor in functional bowel disorders (27).The GI microbiota is the microbe population living in our intestine. It contains tens of trillions of microorganisms, including at least 1000 different species of known bacteria. Microbiota can, in total, weigh up to 2 kg. One third of our GI microbiota is common to most people, while two thirds are individually unique (109). Diet profoundly affects gut microbiota and many of the effects of the diet on gut function can be modified by the gut microbiota composition and function (110). Therefore, manipulation of gut microbiota through dietary changes has been put forward as one promising treatment option for IBS in the future. Moreover, part of the variance in response to different dietary manipulations may be due to differences in gut microbiota composition.

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Diet and lifestyle changes are important management strategies in IBS.

However, few randomized controlled trials exist on dietary treatment of IBS patients. Instead, the current recommendations are primarily based on studies assessing physiological function in relation to dietary components (57, 111).

In 2012, the British Dietary Association published evidence-based guidelines for the dietary management of IBS in adults (112), even though these were mainly based on non-randomized trials. A comprehensive literature search was conducted and relevant studies from 1985 to 2009 were identified and critically appraised. Three lines of dietary management were identified where the first line includes clinical and dietary assessment and advice about healthy eating and lifestyle management, including physical activity and also some general advice on lactose and non-starch polysaccharides. In the second line there were more advanced dietary interventions to reduce IBS symptoms, which include non-starch polysaccharides, FODMAP and also recommendations about probiotics. The third line included elimination diets.

In the conclusion the authors raised the need for adequately powered randomized controlled trials on different dietetic strategies in the future.

Some of the currently used approaches to dietary advice in IBS are briefly discussed below.

An increase of dietary fibers has been widely advocated as a first-line treatment in IBS, based on the effect on stool form and consistency, but with contradictory results. This advice was based on positive initial results of a diet with high wheat-fiber content on IBS symptoms (86). However, several studies failed to confirm these positive results (113, 114), and a survey of IBS patients later found that 55 % of the patients even reported a deterioration by bran, whereas only 10 % found it helpful (87). These disappointing results of an increased fiber intake in IBS patients may be related to an abnormal colonic fermentation (115). Today the advice regarding increasing fiber intake is mainly proposed to patients with constipation as their main complaint, and to use soluble fibers, particularly ispaghula or psyllium, instead of the insoluble fiber wheat bran (116).

Soluble fibers, which is prevalent in several fruits, such as apricots, figs and prunes, have a greater water-holding capacity than insoluble fibers and a

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more pronounced effect on fecal bulking, which is probably beneficial for IBS patients.

A majority of patients with lactose intolerance can consume a considerable amount of lactose before having symptoms (117), and the use of enzymatic treatment (lactase supplements) seems to be of limited value (118).

Therefore, perceived lactose intolerance could be relevant only for a subgroup of IBS patients. In these patients a lactose reduced diet might have a positive effect on some of the symptoms, especially diarrhea and gas/bloating, but the general impression is that the importance of lactose intolerance in IBS have been overestimated during the past.

Up to 96 % of individuals with IBS state that abdominal bloating occurs (119), and is the most bothersome symptom in a large proportion of the patients (120). Abdominal bloating increases in severity during the day, when eating and then settles overnight (119, 120). There is good evidence that intake of fermentable carbohydrates, FODMAPs, could increase the severity of bloating, but also loose stools in IBS subjects (121, 122). Avoidance of FODMAPs is therefore recommended in order to reduce symptom severity of bloating and other GI symptoms observed, and this recommendation is based on controlled clinical trials (123). However, available treatment trials have either used a standard or habitual diet as comparator, without the aim to improve symptoms with this comparative diet (96, 97), or used a non- randomized, non-blinded study design (64). This dietary regime requires specialist dietetic knowledge for successful compliance and detailed information on which food to avoid. The first 2-8 weeks the diet is proposed to be as strict as possible in order to achieve symptom relief, and thereafter a planned and systematic re-introduction of foods high in fermentable carbohydrates is recommended (64). In order to have an adequate dietary regime in the long run, it is considered essential to reintroduce foods containing FODMAPs to identify the carbohydrates that are tolerable on an individual basis and those that trigger symptoms. The reintroduction should include one FODMAP at a time during three days. If no symptoms occur with e.g. honey (fructose), a challenge with the next FODMAP during three days can be pursued. The method demands perseverance and careful planning together with a dedicated and well-informed supervisor, and so far no clinical trials demonstrating that this approach with reintroduction is effective and how this should be done exist. All clinical trials assessing the effect of low FODMAPs diet in IBS are 2-4 weeks. Moreover, FODMAPs, as well as resistant starch, are suggested to have positive physiological effects on

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colonic health, which may lower disease risk just like prebiotics (124).

Recent studies have shown that low FODMAPs diets have led to alterations in colonic luminal microenvironment (104, 125), which potentially may have negative health effects long-term, but this needs to be addressed in prospective follow-up studies. Therefore, health implications and functional significance of reduced intake of fermentable carbohydrates might lead to caution about reducing the intake of FODMAPs in the long term and the restriction of such carbohydrates only to the level of adequate symptom control is recommended.

One interesting approach that would reduce the need to follow a strict carbohydrate restricted diet in order to improve symptoms would be to administer an enzyme that could digest poorly digested carbohydrates, and thereby facilitate absorption in the small intestine. This approach is currently used for lactase deficiency, where lactase can be administered (100). Į- galactosidase is an enzyme with amylase-like activity, which has been reported to be effective in reducing gas production and relieving gas-related symptoms after meals rich in incompletely absorbed carbohydrates (126- 128). The enzyme is derived from the mold Aspergillus niger and can break down fructans and GOS in the small intestine before they are metabolized by colonic bacteria. By this mechanism Į-galactosidase has the potential to facilitate the intestinal absorption and to minimize the bacterial gas production of these carbohydrates. This enzyme has been tested in healthy subjects and in children with IBS, with a reported reduction in GI symptoms, particularly gas-related complaints, when ingested in conjunction with meals (126-129). However, it is not yet established if Į-galactosidase is efficient in alleviating GI symptoms in adult patients suffering from IBS.

The gut microflora can be an important part in the pathophysiology of IBS and a modulation of this environment may improve symptoms (130). There is emerging but conflicting evidence for the use of probiotics in IBS (131).

Even though the overall effect is modest and probiotics are unlikely to be beneficial for all IBS patients, it seems as some probiotics are favorable in improving symptoms. However, the preferred probiotic strains, products, and regimen of use are not clear (132, 133).

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Most patients with IBS have made alterations in their diets, which in some cases may be extreme. Food elimination diets have been used to identify food intolerance or allergy in individuals with IBS. However there are no standard diet describing which foods should be excluded, and this diet should only be tried when single food avoidance has not improved symptoms and when multiple food intolerance are suspected (111). Food elimination diets are time consuming for the patient and for the practitioner, as it usually take 3-4 months to complete, including re-introduction phase. The elimination diet requires a high degree of motivation and compliance (65, 134). Potentially offending foods can only be identified after elimination and subsequent reintroduction. A detailed review is required after completion of the elimination diet and food reintroduction phase to assess the nutritional adequacy of the diet. However, existing studies with elimination studies in IBS show conflicting results (65, 111, 135-138), and in current recommendations and narrative reviews on dietary advice in IBS, extensive elimination diets are not recommended (4, 57).

There is one study that have used a food elimination diet based on IgG antibodies to various foods in IBS patients with good results (134), but no study has reproduced these findings, and another study found no association between IgG to various foods and symptoms (139), so this approach is still controversial.

Other common dietary advice often includes reducing the intake of coffee and fat, despite the fact that randomized controlled studies supporting this are lacking (57). This is instead based on studies assessing physiological function in relation to these dietary components (78, 140), and to a lesser degree upon research examining the role of dietary components in the therapeutic management of IBS patients. Moreover, eating small, frequent meals, rather than large, infrequent meals are often recommended, which is also based on GI physiologic effects of larger versus smaller meals (79, 80). Another approach that is gaining popularity is to reduce the gluten content in the food, but as stated above, the evidence supporting this dietary approach in patients without celiac disease is controversial (108).

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The overall aim of this thesis was to acquire a better understanding of the nutrient intake in IBS patients and impact of food on IBS symptoms, in order to improve dietary advice given to patients suffering from this condition.

To determine the nutrient intake in IBS patients in comparison with the general population, as well as evaluating if their nutrient intake meet nutrition recommendations.

To determine which food groups and specific food items IBS patients report to cause GI symptoms, and to investigate the association with GI, extraintestinal and psychological symptoms, as well as with quality of life.

To assess if the enzyme Į-galactosidase is superior to placebo in reducing GI symptoms and intestinal gas production after ingestion of carbohydrate-rich meals in adult patients with IBS.

To compare the effects on IBS symptoms between a low FODMAPs diet and traditional dietary advice in patients with IBS.

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Papers I-II. We included patients with IBS according to the Rome III (5) criteria, who participated in treatment trials and in a study assessing the relative importance of different pathophysiological factors in IBS at the gastroenterology outpatient clinic at Sahlgrenska University Hospital. The patients completed questionnaires as part of the baseline evaluation in these trials. We excluded patients with other severe diseases that were likely to have an impact on nutrient intake and GI symptoms.

Paper III. IBS patients that previously had taken part in studies at the gastroenterology outpatient clinic at Sahlgrenska University Hospital were invited take part in this study. They were already diagnosed with IBS according to the Rome III criteria (5), and had specific complaints of frequent bloating, abdominal distension and/or flatulence determined by the Rome III Modular questionnaire (141) and the distension/bloating sub-score of the IBS Severity Scoring System (IBS-SSS) questionnaire (142).

Paper IV. We recruited IBS patients meeting the Rome III criteria (5) from the gastroenterology outpatient clinics at Sahlgrenska University hospital in Gothenburg, Karolinska University Hospital and Sabbatsbergs Hospital in Stockholm. In Gothenburg the patients were also recruited through advertisement in the local newspaper. We excluded patients with other severe diseases that were likely to have an impact on symptom generation, and also patients that already followed a diet excessively restricting certain nutrients.

All patients completed questionnaires at different stages of the studies as specified below.

In Papers I-IV the patients completed the IBS-SSS (Figure 1). This questionnaire assesses the severity of IBS symptoms during the previous ten days. The score ranges from 0 to 500. %\XVLQJ³FXW-RIIYDOXHV´WKHSDWLHQWV

were divided into three groups; < 175 mild IBS; 175 ± 300 moderate IBS;

and > 300 severe IBS (142).

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Figure 1. Schematic figure demonstrating the included items in IBS-SSS.

Moreover, in Paper III, a modified version of the IBS-SSS was completed in the morning, the day after each test day, in order to specifically assess the effects of the study medication. The modified questionnaire version included only the current experience of severity of abdominal pain, abdominal distension and dissatisfaction with bowel habits.

In Paper IV the patients recorded all bowel movements in a stool diary, based on BSF, the Bristol Stool Form scale (5), every day during the screening period, as well as during the intervention period. The stool frequency was recorded as number of stools per day and the BSF scale was used to assess the mean stool consistency. Information from the stool diaries were used to subtype IBS patients according to Rome III, (5), and to assess changes in stool frequency or consistency during the intervention period compared to baseline. This form had also been used in Paper I-II to subtype patients.

In Paper III, the severity of eight GI symptoms were rated (scores from 0 to 20) in a symptom-questionnaire; gas, bloating, abdominal discomfort, abdominal distension, nausea, stomach rumbling, urgency to have a bowel movement and abdominal pain. This questionnaire was completed each half- hour during test days (143).

IBS Symptom Severity Score (IBS-SSS)

Abdominal pain intensity

Life interference Dis-

satisfaction with bowel

habit Abdominal

distension Abdominal

pain frequency

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In Papers I and II patients completed the Hospital Anxiety and Depression (HAD) scale to assess severity of general anxiety and depression, respectively (144). For the analyses in Paper I we used the HAD scale cut-off scores to define patients with and without clinically significant anxiety and depression VFRUH.

In Papers II and IV, the Visceral Sensitivity Index (VSI) was used to measure GI symptom-specific anxiety (22, 145). Higher scores on both of these scales assessing general and GI-specific anxiety, and depression, indicate more severe symptoms.

In Paper IV, the Multidimensional Fatigue Inventory-20 (MFI-20) (146) was used to assess the severity of general fatigue, physical fatigue, reduced activity, reduced motivation and mental fatigue. A higher score indicates more severe fatigue.

The Irritable Bowel Syndrome Quality of Life Questionnaire (IBSQOL) was used in Paper II to measure effects of IBS symptoms on quality of life, divided into nine dimensions (147). A low score implies poor quality of life.

The patients in Paper II completed a questionnaire assessing the occurrence of symptoms from intake of 56 different food items or food groups, without any severity grading. This questionnaire is frequently used clinically at the department of allergology at Sahlgrenska university hospital as an assessment tool of food intolerance. The included food items or food groups were chosen to include relevant foods implicated in food allergy and intolerance (53, 148- 150). The foods were grouped according to different potential underlying mechanisms/content responsible for symptom generation, such as foods containing incompletely absorbed carbohydrates, fat, biogenic amines, lectins, preservatives or having a potential to release histamine or to cross- react with airborne allergens (Figure 2). Only food items reported to cause GI symptoms were included in the analyses (Paper II). The results were used to assess the proportion of subjects reporting GI symptoms as well as the number of food items reported to cause GI symptoms in each individual as a measure of the degree of self-reported food intolerance.

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Figure 2. Foods in the self-reported questionnaire responsible for symptom generation.

Papers I and IV. The IBS subjects were given thorough instructions from a dietitian in order to accurately complete a food record. The dietary intake data was obtained for four days; 3 consecutive weekdays and one connected weekend day (Paper I) or Wednesday-Saturday (Paper IV). Patients were instructed to consume their usual diet, to enter time of the food intake, the specific food item, and to enter the amount in the food diary as accurately as possible (in grams or household measures). All food items and beverages were entered in the software Dietist.XP version 3.1 (Kostdata.se, Stockholm, Sweden), which converts food items into nutrients and energy amounts.

Benzoic acid

Sour milk/yoghurt Orange Lingonberry

Amines

Cheese

Fish Wine/beer Orange

Chocolate

Tomato Salami Bananas Avocado

Incomplete absorbed carbohydrated

Peach

Plum Cherries

Apple Pear

Potato Peas

Nectarine

Apricot Beans/lentils

Peanuts

Wheat flour

Other flour Milk

Sour milk/yoghurt Cheese

Chocolate

Celery Bananas

Avocado Dried fruit

Birch related

Hazelnuts

Brazil nuts Walnuts

Almonds Kiwi

Cherries

Plum

Potato Pear Apple

Apricot Nectarine Carrots

Celery Peach

Grass- related

Tomato

Histamin-releasing

Milk Egg

Fish Pork

Wine/beer Strawberries Orange Shellfish Tomato

Chocolate Sulfites

Dried fruit Wine/beer

Ragweed

Melon Bananas

Mugwort- related

Carrots

Bell pepper Anise/caraway

Curry

Chamomile Coriander

Parsley Celery

Sunflower seeds

Melon

Capsaicin- containing

Cayenne/red pepper Chili/tabasco Bell pepper

Lectins

Potato Soy

Soy Peas

Beans/lentils Peanuts

Wheat flour

Mite- related

Shellfish

Latex-related

Chestnut Avocado

Melon Kiwi Bananas

Peach Tomato

Melon

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Composite foods were split into ingredients. From the 4-days food records, average daily intakes were calculated.

In Paper IV, a new Swedish database was used in addition to Dietist.XP, to assess the content of lactose, fructose, galacto-oligosaccharides, fructans and polyols (Liljebo et al. Manuscript in preparation).

Paper I. To assess the nutritional intake of the general population we used data from a national dietary survey, ³5LNVPDWHQ´ conducted in 1997-1998, where the participants had completed a pre-coded food diary with pre-printed alternatives for food items, and meal components. They had access to a portion-guide with food photographs to estimate amounts of food, together with amounts in household measures, pieces, etc. Analysis of the data from the food registration of the national dietary survey was performed using the software MATs, version 4.03 (Rudans Lättdata, Västerås, Sweden), which covers around 1700 foods and 48 nutrients.

Paper III. The breath test is a non-invasive test that can detect hydrogen and methane gas produced by bacterial fermentation of unabsorbed carbohydrates that is excreted in the breath. Hydrogen is derived only from bacterial metabolism in the intestine, and methane is produced through consumption of hydrogen by methane-producing bacteria, methanogens (151, 152).

Samples of expired air were collected each half-hour during test days to assess the concentrations of hydrogen and methane in parts per million (ppm). All breath samples were end-expiratory and collected in a system used for the sampling and storing of alveolar air (GaSampler System, QuinTron Instrument Company, Milwaukee, WI, USA). Analysis was immediately done by use of a gas chromatograph (QuinTron Breath Tracker, QuinTron Instrument Company, Milwaukee, WI, USA).

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Paper III. The participants arrived in the morning the test day and completed questionnaires. The patients were randomized to receive three capsules containing the digestive enzyme Į-galactosidase (Nogasin^®, Oy Verman, Kerava, Finland) or a corresponding placebo with identical capsule design before start of three study specific meals at both of the study days. Each capsule with the active enzyme had a total content of 400 galactosidic units (GaUI) where 1 GaUI equals the amount of enzyme that releases 1 µmol of galactose from the substrate in 1 min. The dose of the enzyme given at each meal during the active treatment day by consequence was 1200 GaUI. They were served a carbohydrate-rich breakfast and lunch together with enzyme or placebo (Table 3, Figures 3 and 4). Symptom registration (the meal-related GI symptoms questionnaire, see above) and breath samples were collected every half hour for 7.5 hour in all participants. In the evening at home the patients were instructed to eat a prefabricated dinner meal. Two weeks later the procedure was repeated, however, the content of the capsules was the opposite from the first visit. The patients completed the IBS-SSS questionnaire before breakfast each test day and also the modified IBS-SSS the morning after test day (before breakfast).

Table 3. The composition of the test meals.

Time Food Nutrients

Breakfast 8.00

Rye porridge, jam, lactose free- milk

Wholemeal bread, margarine, cheese, bell pepper Apple juice

736 kcal 15.2 g protein 18.0 g fat

108.3 g carbohydrates Lunch

11.30

Chicken and bean casserole

(contents; beans, chickpeas, onion, garlic, tomato, chili, mushrooms, rape oil, black pepper, salt, stock cube, thyme) White bread (wheat), margarine, cheese

Apple juice

697 kcal 52.0 g protein 19.1 g fat

73.0 g carbohydrates Supper Fish au gratin (prefabricated)

Apple juice 780 kcal

50.1 g protein 22.5 g fat

90.1 g carbohydrates

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Figure 3. Rye porridge breakfast.

Figure 4. Bean- and chicken casserole lunch. White bread (wheat), margarine, cheese and apple juice are missing in the picture.

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Paper IV. Patients with IBS were randomized to receive dietary advice from a dietitian about one of two different diets: a low FODMAPs diet or traditional IBS dietary advice and to follow these diets for four weeks (Tables 4 and 5).

The subjects were provided with both verbal and written instructions in the form of a pamphlet with detailed information of which foods to avoid and of alternative food items that could be ingested instead. The patients were blinded to the identity of the dietary advice (called “diet A” and diet B”, respectively). Symptom severity was assessed using the IBS-SSS and patients completed a 4-days food diary during screening and during the last week of the intervention period. A responder to the intervention was defined as a patient who demonstrated a reduction of the total score of the questionnaire IBS-SSS ≥ 50 at the end of the treatment period (day 29) compared with baseline (day 0).

Table 4. A selection of instructions from the low-FODMAP diet (“Diet A”).

Food to avoid Suitable foods

High in fructans and/or GOS

Cereal grains (wheat, rye, barley) Rice, potato, oats, polenta, quinoa, buckwheat Bread and pasta (white, wholemeal) Wheat free or gluten-free bread and pasta

Beans and pulses Green beans

Garlic and onions Spring onion (green part), herbs

Nuts and seeds; cashew, pistachios Peanuts, pecans, walnuts, sunflower seeds High in polyols

Apple*, pear*, nectarine, plum, prune Banana, orange, kiwi, honeydew melon Cauliflower, mushroom, sweet corn Carrot, parsnip, cucumber, spinach, lettuce Sugar-free products with sorbitol, xylitol,

mannitol

Sugar, glucose syrup, dextrose

High in fructose

Mango, apple*, pear*, watermelon, honey Pineapple, strawberries, blueberry High in lactose

Milk, yoghurt, ice cream Lactose free milk, yoghurt, ice cream

Food to limit

Coffee, alcohol, carbonated drinks Non-caffeinated drinks, water, non-fizzy drinks

*Some food items contain more than one type of FODMAP, i.e. apples and pears are rich in fructose as well as polyols.

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Table 5. A summary of the traditional ,%6GLHW³'LHW%´.

Papers I-II were retrospective studies which partially are based on the same study population (Table 6).

x In Paper I we assessed the nutrient intake of IBS patients in order to investigate if they had a different intake compared to the general population. We also investigated if the intake differed between subgroups of IBS patients based on IBS severity, presence of absence of depression or anxiety, and the IBS subtype based on the predominant bowel habit.

x In Paper II we evaluated the I%6 SDWLHQWV¶ VHOI-reported symptoms from different food items and food groups. In relation to these reported food-related GI symptoms we investigated how levels of anxiety and depression, severity of IBS and somatic symptoms and quality of life influenced the perceived food intolerance, measured as the number of food items reported to cause GI symptoms.

Papers III-IV were prospective studies (Table 6).

x In Paper III we performed a randomized, double-blind, placebo-controlled, cross-over study to assess if Į- galactosidase alleviates symptoms after intake of carbohydrate-rich meals. The patients were served two

Dietary advice

x Eat regular meals

x Do not skip meals or eat late at night

x Take your time when eating, chew your food well

x Limit fatty foods, spicy foods, onions, legumes, coffee and alcohol x Avoid carbonated drinks, chewing gum and sugar-free products x If constipated: increase the amount of dietary fibers as well as fluids.

x If diarrhea: limit intake of dietary fibers, berries are often better than fruits, cooked vegetables better than raw

x Continue eating probiotics, however, do not start eating probiotics during the study period